Wednesday, February 29, 2012

Good Afternoon Folks,
Today on the blog is an abstract from Medscape showing data on a small phase II study using the interferon free combo BMS-790052-Daclatasvir/BMS-650032-Asunaprevir. Last month an interesting article discussing concerns about the study appeared at Medical Lessons. The author Elaine Schattner, MD., points us to the phase II study published at New England Journal of Medicine, the author writes:

A recent New England Journal of Medicine delivered an intriguing, imperfect article on a new approach to treating hepatitis C (HCV). The paper's careful title, Preliminary Study of Two Antiviral Agents for Hepatitis C Genotype 1, seems right. The analysis, with 17 authors listed, traces the response of 21 people with hepatitis C (HCV) who got two new anti-viral agents, with or without older drugs, in a clinical trial sponsored by Bristol-Meyers Squibb.

I have several concerns about this report. One is that the researchers screened 56 patients for possible registration but enrolled only 21 on the trial; according to a supplementary Figure 1, 35 potential subjects (over half) didn't meet criteria for eligibility. This disparity makes any once-researcher wonder about bias in selecting patients for enrollment. If you're a pharmaceutical company and want to show a new drug or combo is safe, you're going to pick patients for a trial who are least likely to experience or display significant toxicity.

Toxicity seems like it could be problematic. Diarrhea, fatigue and headaches were common among the study subjects. Worrisome is that six patients (of 21, that would be 28.5% of those on the trial) had liver problems manifest by at least one enzyme (the ALT) rising over three times the normal limit.

Introduction
The current generation of direct acting antivirals (DAAs), telaprevir and boceprevir, in combination with peginterferon and ribavirin (PEG/RBV) have demonstrated limited efficacy in patients with hepatitis C virus (HCV) genotype 1 infection who have experienced a previous null response to PEG/RBV. Sustained virologic response (SVR) has been approximately 30%, with associated high rates of resistance. Now, researchers have explored the efficacy of two next-generation DAAs with and without PEG/RBV in this patient population.

Ten patients received both DAAs and PEG/RBV for 24 weeks (DAA+PEG/RBV group). Of note, 90% of the study cohort had IL28B genotypes CT or TT, which respond poorly to PEG/RBV. The primary endpoint was SVR at 12 weeks after stopping therapy.

The SVR in the DAA-only group was 36% (2 of 9 with genotype 1a and 2 of 2 with genotype 1b). Six patients, all with genotype 1a, had viral breakthrough that was associated with viral resistance mutations to both DAAs.

Alternately, the SVR in the DAA+PEG/RBV group was 100% (90% with genotype 1a) at 12 weeks after therapy and 90% at 24 weeks. Most adverse events were mild to moderate and included diarrhea, fatigue, headache, and nausea.

These findings provide early evidence that the next generation of DAAs is more potent than the current generation in treating HCV genotype 1 infection.

In this cohort of the most difficult-to-treat HCV patients — previous null responders with genotype 1 infection — a 24-week SVR of 90% was achieved after 24 weeks of quadruple therapy (2 DAAs and PEG/RBV). Even an interferon-free regimen of the 2 DAAs resulted in an SVR of 36%.

Results are eagerly anticipated from the phase III trial currently under way.

Researchers from the Mayo Clinic confirm that ultrasound-based transient elastography (TE) provides excellent diagnostic accuracy for detecting cirrhosis due to recurrent infection with hepatitis C virus (HCV) infection following liver transplantation. Findings from the study published in the March issue of Liver Transplantation, a journal of the American Association for the Study of Liver Diseases, suggest that detection of significant fibrosis is more accurate when comparing patients with chronic HCV of the native liver.

According to the World Health Organization (WHO), chronic HCV affects up to 170 million people worldwide and could lead to more severe liver diseases such as cirrhosis and liver cancer. Experts estimate that on average 6,000 liver transplants are performed in the U.S. each year. Medical evidence shows that following liver transplantation recipients who are HCV RNA-positive at the time of transplantation are at risk of reinfection with HCV. Moreover, studies have determined that fibrotic tissue can develop more quickly in the transplanted liver resulting in rapid progression of cirrhosis and graft failure.

"The current gold standard for determining liver disease severity and progression is liver biopsy," explains lead author Dr. Jayant Talwalkar with the Mayo Clinic in Rochester, Minnesota. "However, biopsy following liver transplantation may not accurately determine fibrosis severity and non-invasive imaging technology has advanced to more accurately assess the severity of liver injury which includes an indirect assessment of elevated portal pressure." A prior study reported liver biopsy can understage cirrhosis in up to 30% of cases.

For the present study researchers reviewed studies of the diagnostic accuracy of ultrasound-based TE, a non-invasive technology used to assess fibrosis by measuring liver stiffness. The team analyzed the performance of TE compared to liver biopsy in detecting sever hepatic fibrosis caused by recurrent HCV post-transplantation. Compared to liver biopsy, TE is a reproducible diagnostic technique that is quick and painless for patients.

Six studies were identified, with five studies that evaluated significant fibrosis and cirrhosis. Analysis of the pooled estimates showed TE had a sensitivity and specificity of 83%, respectively for detecting fibrosis. Of the five studies analyzing TE for detecting cirrhosis, sensitivity estimates were 98% and specificity at 84%. "Ultrasound-based TE provides excellent diagnostic accuracy for identifying cirrhosis caused by recurrent HCV following liver transplantation," concludes Dr. Talwalkar. "Further studies that confirm our results could highlight the importance of TE as a diagnostic tool for liver transplant recipients infected with HCV."

This study is published in Liver Transplantation. Media wishing to receive a PDF of the article may contact healthnews@wiley.com.

Author Contact: To arrange an interview with Dr. Talwalkar please contact Brian Kilen with the Mayo Clinic at Kilen.Brian@mayo.edu or 507-266-1161.

About the Journal
Liver Transplantation is published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. Since the first application of liver transplantation in a clinical situation was reported more than twenty years ago, there has been a great deal of growth in this field and more is anticipated. As an official publication of the AALSD and the ILTS, Liver Transplantation delivers current, peer-reviewed articles on surgical techniques, clinical investigations and drug research — the information necessary to keep abreast of this evolving specialty. For more information, please visit Liver Transplantation.

About Wiley-Blackwell
Wiley-Blackwell is the international scientific, technical, medical, and scholarly publishing business of John Wiley & Sons, with strengths in every major academic and professional field and partnerships with many of the world's leading societies. Wiley-Blackwell publishes nearly 1,500 peer-reviewed journals and 1,500+ new books annually in print and online, as well as databases, major reference works and laboratory protocols. For more information, please visit http://www.wileyblackwell.com/ or our new online platform, Wiley Online Library (wileyonlinelibrary.com), one of the world's most extensive multidisciplinary collections of online resources, covering life, health, social and physical sciences, and humanities.

San Francisco—A second Phase IIb study of a new oral therapy for hepatitis C, PSI-7977, taken once daily, increased sustained virologic response (SVR) rates up to 91% in patients with difficult-to-treat hepatitis C virus (HCV) genotype 1 infection—a substantial improvement from the 50% reported in patients who received standard peginterferon and ribavirin (Peg-IFN/RBV) therapy. The study also showed significant advantages of PSI-7977 in patients who typically have poor responses to interferon.

Investigators say the new drug has the potential to dramatically alter the treatment paradigm for patients with hepatitis C virus (HCV) infection. “That’s true for all genotypes and all patients,” said lead author Eric J. Lawitz, MD, medical director of Alamo Medical Research, in San Antonio.
Patients who have the interleukin-28B (IL28B) TT genotype generally have a much lower chance of responding to IFN than people with the CC or CT genotypes. Yet in this study, these patients achieved high SVR rates to PSI-7977. Of the 13 patients who carried the TT allele, all tested negative for HCV by the third week of treatment and achieved SVR at week 12.
“The high SVR of greater than 90% in HCV genotype 1 patients was independent of predictors of poor IFN response,” Dr. Lawitz said.

Results from the two studies sparked considerable excitement among attendees of The Liver Meeting about this investigational therapy.

“I think it’s proof of principle that the proper combination of direct-acting antivirals can, in fact, produce enough suppression of viral replication to result in extinction of infection without the benefit of a broadly acting antiviral like IFN,” said Raymond Chung, MD, chief of hepatology and vice-chief of gastroenterology at Massachusetts General Hospital, in Boston.
The PROTON study was designed to examine dose-dependent response rates for PSI-7977 in HCV genotype 1–infected patients. Investigators enrolled 121 treatment-naive patients with this genotype in a randomized, double-blind, placebo-controlled, dose-ranging fashion. All patients were at least 18 years old with an HCV RNA level of 50,000 IU/mL or greater, platelets greater than 90,000/mm3, neutrophils greater than 1,500/mm3, and a hemoglobin level of at least 11 g/dL, with no evidence of cirrhosis.

Trial participants were randomized in a 2:2:1 ratio to one of three treatment arms: PSI-7977 200 or 400 mg daily in combination with IFN and RBV (n=48 and n=47, respectively) or Peg-IFN/RBV alone (n=26). Patients in the PSI-7977 arms received triple therapy for 12 weeks, followed by an additional 12 weeks of Peg-IFN/RBV. All patients who achieved early rapid virologic response (RVR) discontinued therapy at 24 weeks, while all others continued therapy for a total of 48 weeks. Patients in the IFN and RBV arm received treatment for 48 weeks.

Analysis showed robust response rates among all PSI-7977 patients regardless of dose. Patients who received 200 mg daily showed an RVR rate of 98%, an early RVR rate of 98% and an end-of-treatment response rate of 91%. Patients receiving 400 mg showed a 98% RVR, 91% early RVR and 91% end-of treatment response through 24 weeks. In contrast, response rates among patients who received Peg-IFN/RBV alone were 19%, 50% and 50%, respectively.

In an as-treated analysis of patients who received at least eight weeks of PSI-7977, 88% of those in the 200-mg arm and 98% of those in the 400-mg arm achieved an SVR at 12 weeks.

Several failures occurred in the trial.
Three patients in the 200-mg arm who had viral suppression during the first 12 weeks of treatment with PSI-7977 experienced a virologic breakthrough during the follow-up treatment period with Peg-IFN/RBV. No breakthroughs were observed among patients in the 400-mg arm, although one patient had a viral relapse before SVR at 4 weeks. “This suggests that [the] 400-mg dose achieved a deeper viral suppression,” said Dr. Lawitz.

The extent of viral suppression may be the key difference between the 200- and 400-mg doses of PSI-7977, he said. PSI-7977 at a 400-mg dose may provide a more thorough viral suppression with lower risk for virologic breakthrough. Patients in both groups quickly became negative for HCV RNA after PSI-7977 was started, but patients who received the 200-mg dose had more virologic breakthroughs after the PSI-7977 therapy was completed. No patient in either treatment arm developed an S282T mutation.

Investigators said they were pleased to see that the adverse events reported in the PROTON trial were typical of those seen with Peg-IFN/RBV treatment, except for a small increase in insomnia. Overall, 15% of patients in the 400-mg arm and 8% of those in the Peg-IFN/RBV–only arm reported insomnia.

More cases of neutropenia occurred with PSI-7977 than with Peg-IFN/RBV, but it was unlikely that the difference was significant, said the investigators. Three patients who received PSI-7977 had grade IV neutropenia compared with none in the Peg-IFN/RBV arm. However, the numbers of patients were too low to result in meaningful conclusions.

Still, experts say more patients must be studied to confirm that the new drug is safe.

“The numbers for neutropenia and anemia are confusing to me. They are small numbers but I’m still not certain about the safety of this compound,” said Paul Pockros, MD, head of gastroenterology and hepatology, and director of the Center for Liver Diseases, Scripps Clinic, in La Jolla, Calif.
The study was not powered to detect differences in neutropenia and anemia between the three groups, but differences would be statistically significant if 1,000 patients had participated in the trial, Dr. Pockros explained. “Is this drug going to be safe in 1,000 patients?” he asked.

Dr. Lawitz said investigators would expect to see a difference in adverse events between the 200- and 400-mg arms in this trial if PSI-7977 increased the risk for neutropenia, but that was not the case, with more neutropenia and anemia occurring in the patients receiving the lower dose.
“To me, that suggests that this is a trial with small numbers, and when we get larger numbers the difference is probably not going to be significant,” he said.

PSI 7977, in combination with RBV as dual therapy, is set to enter Phase III trials

In The News

Math Can Save Tylenol Overdose Patients
New Way for Docs to Predict Who Needs Liver Transplants

Source University Of Utah
Feb. 27, 2012 – University of Utah mathematicians developed a set of calculus equations to make it easier for doctors to save Tylenol overdose patients by quickly estimating how much painkiller they took, when they consumed it and whether they will require a liver transplant to survive.

“It’s an opportunity to use mathematical methods to improve medical practice and save lives,” says Fred Adler, a professor of mathematics and biology and coauthor of a study that developed and tested the new method.

The study of acetaminophen – the generic pain and fever medicine sold as Tylenol and in many other nonprescription and prescription drugs – was set for publication within a week in Hepatology, a journal about liver function and disease.

Adler, math doctoral student Chris Remien and their colleagues showed that using only four common medical lab tests – known as AST, ALT, INR and creatinine – the equations can quickly and accurately predict which Tylenol overdose patients will survive with medical treatment and which will die unless they receive a liver transplant.

The researchers analyzed the records of 53 acetaminophen overdose patients treated at the University of Utah’s University Hospital to test the equations and show they quickly and accurately predicted, in retrospect, which patients survived and which died.

Speed is essential in listing acute liver failure patients as candidates for transplant, says study coauthor Norman Sussman, a former University of Utah liver doctor now at the Baylor College of Medicine in Houston.

If a doctor is uncertain and starts to treat an acetaminophen-poisoning patient with the antidote to combat liver failure – even though the patient may not survive with such medicine – their odds for getting a new liver are reduced.

“If I wait another day until I list them for transplant, the chance of getting a liver is that much lower,” Sussman says. “If you’re going to get someone transplanted, you have to do it fast or you miss the boat. The patient may pass the window when transplants can be done. They become too sick and can’t stand the transplant.”

The new method using calculus equations will let doctors rapidly determine if a patient can survive with antidote treatment or will die unless they get a transplant.

The study urges another clinical trial to prove the new method’s usefulness. Sussman plans to start a one-year prospective trial testing the method on 50 patients at the University of Utah and three hospitals in Houston.

If that trial proves the method can accurately predict ahead of time how Tylenol-poisoning patients will fare, “we believe we could create a tool available and immediately useful to clinicians,” Sussman says. Adler foresees a smartphone application.

Adler, Remien and Sussman conducted the study with University of Utah hepatologist Terry Box and Lindsey Waddoups, clinical research coordinator for the University of Utah’s gastroenterology division. The research was funded by a National Science Foundation grant to the University of Utah’s program in mathematical biology.

Painkiller Can Be a Killer

Acetaminophen – the primary generic name for the drug also known generically as APAP and paracetemol – is found in prescription medicines such as Tylenol with Codeine, Percocet or Vicodin, and in dozens of over-the-counter medications, including Tylenol, Anacin, Pediacare, Triaminic and combination cold medications like Nyquil.

Many people don’t realize the common analgesic can destroy the liver and kill at only about five times the recommended dosage – a narrow margin in medical terms.

“Acetaminophen is the leading cause of acute liver injury in the United States, accounting for some 56,000 emergency room visits, 26,000 hospital admissions and about 500 deaths annually,” Adler and his coauthors write.

The current maximum dose of acetaminophen is 4 grams (4,000 milligrams or eight 500 milligram tablets, for example) in 24 hours. There is not a lot of room for error between that 4-gram maximum and the 6 grams that can cause liver damage or the 20 grams that are considered likely to destroy 70 percent of liver cells and cause death.

Acetaminophen overdoses can be treated successfully if an antidote named N-acetylcysteine (N-Ac or “nack”) is administered within roughly 24 hours. After a certain time post-overdose, treatment becomes futile and the patient will die without a transplant.

Yet many overdose patients are confused or comatose, unable to say how much acetaminophen they took or when they took it, making it tough to predict their prognosis.

Life-Saving Calculus

The new method uses eight main “differential equations” – basic calculus equations that describe how changes in one variable affects changes in another variable over time. The equations simulate or “model,” step-by-step, how acetaminophen is metabolized in the liver, including production of NAPQI, a liver-destroying substance.

That makes it the first known “dynamical” model based on real biology – a contrast to the existing “statistical” method for determining how overdose patients fare.

The statistical method – known as the King’s College Criteria (KCC) – estimates who is likely to survive or die from acetaminophen toxicity using correlations between INR and creatinine lab tests and which patients actually did live or die in the past. The King’s College Criteria predict liver failure if INR exceeds 6.4, creatinine exceeds 3.4 and there is confusion, altered consciousness or coma due to liver damage.

The problem, says Adler, is the criteria “look at the statistical relationship between lab test results and patient outcome without understanding what’s happening inside the liver. It’s just statistics.”

The new method “tracks how the liver’s health changes over time,” he says.

The new equations use patients’ measured levels of AST, ALT and INR to estimate when they consumed acetaminophen and how much they took. By also considering creatinine levels, the new method accurately predicts which Tylenol overdose patients will survive with treatment and which will require a liver transplant to avoid death.

AST (aspartate aminotransferase) and ALT (alanine aminotransferase) are enzymes that are released by dying liver cells, so higher levels indicate liver damage. INR (prothrombin time/international normalized ratio) measures how fast blood clots. Liver cells make clotting factors, so if the liver malfunctions, clotting is slower. Creatinine is a measure of kidney dysfunction, in this case secondary to liver damage.

Sussman says the King’s College Criteria are outdated and have grown less useful over time. When a patient arrives with lab results indicating liver failure, “your first decision has to be, ‘Do I list this patient for transplant?’” he says. “That was the purpose of the King’s College Criteria. You need to make an immediate decision: Do I think this patient will live or die? If I think they’ll live, I’m going to treat them [with the antidote]. If they’re going to die, the next question is, are they a candidate for transplant?”

“Our goal was to try to trace it back to: when did the damage start?,” he adds. “Once you know that and the peak damage reflected in the ALT, then you have the tools to predict survival or death.”

Of people who are liver transplant candidates, those with acute liver failure – half due to acetaminophen poisoning – go straight to the top of the liver transplant list, ahead of the vast majority of candidates who have chronic liver failure, such as from alcoholism, Sussman says.

Predicting Overdose Outcomes

The 53 patients whose records were analyzed for the new study varied in alcohol use, malnutrition status and whether they took too much acetaminophen in a suicide attempt, an accidental single overdose or a chronic, multiple-day overdose.

Two patients got liver transplants and were excluded from the analysis “because we don’t know if they would have died or recovered without transplant,” Remien says.

Of the 51 remaining patients, eight died and 43 survived. The study showed that when AST, ALT and INR tests on admission were crunched through the equations, and when creatinine levels exceeded 3.4, the method was highly accurate in predicting, retrospectively, whether overdose patients lived or died. Specifically, the method had:
100 percent sensitivity, meaning the method correctly predicted the deaths of all eight patients who actually had died. By comparison, the King’s College Criteria predicted only one of the eight deaths.
67 percent “positive predictive value,” meaning eight patients died out of 12 deaths predicted by the method.
91 percent specificity, meaning the method predicted 39 patients would survive out of the 43 that really did survive.
100 percent “negative predictive value,” meaning the method predicted 39 patients would survive and those 39 did survive.

Sussman says there were multiple reasons for the eight deaths. Some patients arrived too late to be treated, even by a transplant, and others didn’t qualify as transplant candidates, perhaps due to serious drug or alcohol abuse and lack of family support.

About 16,000 people now are on the liver transplant waiting list in the United States. About 5,000 to 6,600 Americans get liver transplants each year.

Adler emphasizes the new method is based on a typical acute liver failure patient and may need refinement to better predict the prognoses of certain special patients, including those taking other drugs, with chronic alcohol use or suffering anorexia.

Hepatitis C: A Deadly Disease with Few SymptomsSource
A new study says deaths from Hepatitis C are increasing, especially among people 45 to 64 years old

A disease you may never have heard of now kills more Americans than HIV, the virus that causes AIDS, according to date from the Centers for Disease Control (CDC). That disease is hepatitis C, a major cause of liver cancer and cirrhosis, which the CDC estimates has infected about 3.2 million Americans.

According to a new report published in the Annals of Internal Medicine, the CDC says that deaths from hepatitis C have been steadily increasing in the last decade with most of the deaths among people aged 45 to 64 years old. The virus is spread through injection drug use, blood transfusions received before screenings began in 1992 and through sexual contact. It can also be passed from mothers to newborns.
A major reason hepatitis C is so deadly is its stealth nature. Up to three-quarters of infected adults are unaware they are suffering from the virus because there are often no symptoms until the liver is damaged, which can take more than a decade.
Some people do have symptoms, which can include:

Jaundice (yellowish eyes or skin)

Difficulty stopping bleeding and easy bruising

Swollen stomach or ankles

Fatigue

Upset stomach

Fever

Loss of appetite

Diarrhea

Light-colored stools and dark yellow urine

Some public health specialists are recommending a one-time screening for all people born between 1945 and 1965 even if they have no symptoms. If you think you may have been exposed to Hepatitis C, ask your doctor for a screening blood test.
Chronic Hepatitis C can be treated effectively with a combination of two protease inhibitors called boceprevir and telaprevir along with interferon and an antiviral drug. The treatment generally takes 24 to 48 weeks.

Washington (CNN) -- An entire class of statin drugs will get new labels that alert the public to safety concerns, the Food and Drug Administration announced Tuesday.
Statins, which treat cholesterol, now will come with labels that include a warning that the drugs, taken by almost 32 million Americans, can cause memory loss and confusion. The FDA says reports in general have not been serious, and the symptoms subsided when patients stopped taking the medications.

The new labeling will also warn doctors and patients that statins can cause hyperglycemia, an increase in blood sugar levels and increase the risk of Type 2 diabetes.
The FDA will no longer recommend routine and periodic monitoring of liver enzymes of patients taking statins. Instead, it said liver enzyme tests should be performed before a patient starts taking statins, and then only when clinically indicated. That's because according to the FDA, serious injury to the liver is rare, and routine monitoring doesn't detect or prevent it. The new label will tell patients who experience fatigue, loss of appetite, dark urine, upper stomach pain or jaundice to notify their doctor immediately.

There also will be a label change specific to lovastatin (Mevacor). Certain medicines interact with this particular statin, increasing the risk of myopathy, or muscle damage. The agency says some drugs should never be taken with Mevacor including protease inhibitors, a class of HIV drugs and certain drugs used to treat bacterial and fungal infections.

Sleeping pills prescribed by your physician are supposed to ward off the myriad health problems that come with lack of sleep.

But adults who take sleeping pills in even small numbers over their lifetimes may be nearly four times more likely to die earlier compared to those who are not prescribed sleeping pills, according to new findings published Monday in the British Medical Journal. And those prescribed sleeping pills may also be more likely to be diagnosed with cancer, the study found.
Researchers looked at electronic medical records of nearly 35,000 patients, fewer than half of whom took such FDA-approved sleep medications as Ambien, Restoril, Lunesta, and Sonata. They found that even those who look fewer than 18 sleeping pills a year were at greater risk of death, compared to those who were not prescribed sleeping aids.

As you may already know, I started Hepatitis C treatment this past Thursday. That means I am now on a very strict schedule when it comes to taking the 12 pills a day and the one shot a week that comprise the treatment. And this new emphasis on being "on time" presents a big new challenge for me too!

Mr C has been down the past few days. Waiting for his CRB to come through so he can start work, being skint and "having nothing to look forward to" is taking its toll. Thankfully, his health is remaining stable and his knee is back on the mend again.

GS-7977 Plus Ribavirin Will Displace the Current Proprietary Clinical Gold Standard, Telaprevir in Combination with Peg-IFNa/Ribavirin, According to Findings from Decision Resources

BURLINGTON, Mass., Feb 28, 2012 (BUSINESS WIRE) -- Decision Resources, one of the world's leading research and advisory firms for pharmaceutical and healthcare issues, finds that, based on clinical data and the opinions of interviewed thought leaders, telaprevir (Vertex's Incivek, Johnson & Johnson's Incivo) in combination with peg-IFNa (Roche's Pegasys or Merck's Victrelis) and ribavirin (Roche's Copegus; Merck's Rebetol; generics) has earned Decision Resources' proprietary clinical gold standard status for the treatment of non-responder patients with hepatitis C virus (HCV). Owing to its competitive advantages in safety and tolerability as well as delivery, the interferon-free combination of Gilead's GS-7977 (formerly PSI-7977) plus ribavirin will displace telaprevir plus peg-IFNa/ribavirin and earn proprietary clinical gold standard status for HCV non-responders in 2015, following its launch for the indication in 2014 in the United States.

Decision Resources' analysis of the hepatitis C virus drug market also finds that surveyed U.S. gastroenterologists and managed care organization (MCO) pharmacy directors agree that the percentage of genotype-1 null responders achieving sustained virologic response is one of the attributes that most influences their decisions regarding prescribing and formulary status determinations, respectively, in HCV non-responders.

According to insights from surveyed U.S. gastroenterologists and MCO pharmacy directors, the absence of interferon-free treatment options for HCV is one of the greatest unmet needs in HCV. Clinical data and the opinions of interviewed thought leaders indicate that GS-7977 has demonstrated the potential to significantly fulfill this unmet need.

The findings also reveal that surveyed U.S. gastroenterologists indicate that they would prescribe the quadruple regimen of Bristol-Myers Squibb's NS5A inhibitor daclatasvir (BMS-790052) plus Bristol-Myers Squibb's protease inhibitor asunaprevir (BMS-650032) plus peg-IFNa/ribavirin to 41 percent of their HCV non-responder patients. Decision Resources' forecast for this quadruple regimen is more conservative due to anticipated reimbursement restrictions, positioning in later lines of therapy, competition from IFN-free regimens and competition asunaprevir will face from other protease inhibitors.

The launch of novel HCV-specific agents will increase the size of the drug-treated population mainly as a result of re-treatment of prior non-responders as well as increased referral and drug treatment rates. The overall HCV drug market will experience significant growth, expanding from almost $1.7 billion in 2010 to $14.4 billion in 2015 in the United States, France, Germany, Italy, Spain, the United Kingdom and Japan. Thereafter, the market will decrease to $11.2 billion in 2020, owing to a decline in the size of the treatment-eligible population due to declining prevalence and effective new regimens.

Decision Resources' Robust Market Forecast and Opportunities Analysis

Decision Resources provides a comprehensive view of what is happening in a specific drug market now and in the decade ahead. The research includes analysis of the unmet need and near-term drug development opportunities that exist within a drug market powered by primary research from physicians and payers. The robust market forecast and opportunities analysis is comprised of the Pharmacor 2012 advisory service and the DecisionBase 2012 report series.

About Decision Resources

Decision Resources ( www.decisionresources.com ) is a world leader in market research publications, advisory services and consulting designed to help clients shape strategy, allocate resources and master their chosen markets. Decision Resources is a Decision Resources Group company.

About Decision Resources Group

Decision Resources Group is a cohesive portfolio of companies that offers best-in-class, high-value information and insights on important sectors of the healthcare industry. Clients rely on this analysis and data to make informed decisions. Please visit Decision Resources Group at www.DecisionResourcesGroup.com .

All company, brand, or product names contained in this document may be trademarks or registered trademarks of their respective holders.

Using a computer model of the hepatitis C disease, Stanford researchers have shown that two new drugs intended to target the virus are cost-effective for patients suffering from advanced hepatitis C, despite some significant side effects.

Hepatitis C, a virus that leads to swelling or inflammation of the liver, is now killing more Americans than the HIV virus. The majority of the 3.2 million people estimated to have chronic hepatitis C in the United States are baby-boomer adults, according to a Scientific American blog.

Jeremy Goldhaber-Fiebert, an assistant professor of medicine, and his research team examined treatments that involved pegylated interferon alongside ribavirin — collectively deemed the standard two-drug therapy — and compared it to a “triple therapy,” with either boceprevir (trade name Victrelis) or telaprevir (trade name Incivek) added to the standard two-drug therapy.

Both drugs entered the commercial market in the summer of 2011, and — though they decrease the chance of chronic hepatitis C — both have severe side effects.

The most common adverse drug reactions to Incivek, as listed by the Food and Drug Administration (FDA), include rash, pruritus, anemia, nausea, hemorrhoids and diarrhea. Victrelis is associated with an additional decrease in hemoglobin concentrations, resulting in fatigue, anemia, nausea, headache and dysgeusia.

The research team, which included graduate students Shan Liu and Lauren Cipriano M.S. ‘11 as well as Professors of Medicine Mark Holodniy and Douglas K. Owens, designed a model to comparatively examine the advantages and disadvantages of three treatment strategies: giving all hepatitis C patients the standard treatment, giving all of them a triple therapy and giving triple therapy only to the patients less likely to respond to standard treatments.

“The computer model we developed includes the health risks, quality of life changes and costs for patients who have genotype 1 chronic hepatitis C infection as well as the effectiveness, costs, side effects [and] quality-of-life changes of undergoing various treatments for chronic hepatitis C,” Goldhaber-Fiebert said. “An expensive treatment, even with some side effects, may be beneficial overall if it is more effective, thereby prolonging life, improving quality and/or averting costs compared to not undergoing treatment.”

Statistical and simulation analysis showed that the new triple therapies were cost-effective for chronic hepatitis C patients with advanced liver disease. For patients with a mild case of the disease, the model’s findings advised determining their IL-28B genotype — associated with gauging whether the standard two-drug treatment will be effective — before deciding on treatment.

“Protease inhibitors increase the effectiveness of standard therapy, but they are costly,” the team’s study states. “A genetic assay may identify patients most likely to benefit from this treatment advance.”

The study links how imminent the threat of severe disease is with justifying the costs and risks of the “triple therapy.”

Despite the costs, universal triple therapy reduced the lifetime risk for liver carcinoma by 38 percent in cases of mild fibrosis and 28 percent in incidents of advanced fibrosis, increasing the quality-adjusted life expectancy by three percent and eight percent, respectively, compared with standard therapy, the study showed.

The study concluded that, “universal triple therapy and IL-28B guided triple therapy are cost-effective when the least-expensive protease inhibitor is used for patients with advanced fibrosis.”

New U.S. statistics show that viral hepatitis deaths are surpassing those from HIV – the virus that leads to AIDS.

This stirring news has helped lead HepCBC Hepatitis C Education and Prevention Society to host a forum to discuss new guidelines for the management of hepatitis C and B recommended by liver specialists.

The forum is being held Friday, March 2 from 9 a.m. to 4 p.m. at Royal Jubilee Hospital’s Begbie Hall, 2101 Richmond Ave.

Five Canadian liver specialists will present new recommended guidelines for managing HCV. Each of their presentations will be followed by a public question and answer and comment period. The public is invited, but as seating is limited, online pre-registration is required via www.hepcbc.ca.

BEIJING -- China says it is sending medical experts to investigate an outbreak of hepatitis C among more than 200 people in the southern province of Guangdong.

Ministry of Health spokesman Deng Haihua said Monday that mistakes in medical procedures may have caused the infections in the province's Zijin county. Deng said strengthened preventative measures were ordered at clinics and hospitals in the area to prevent the further spread of the virus.

Hepatitis C is spread primarily through blood and can lead to life-threatening liver damage. Infection can occur through blood transfusions, poorly sterilized equipment or the sharing of intravenous drug needles.

Use of contaminated needles has been blamed in previous outbreaks in China.

Baby Boomers have one more item to add to their to-do list, and it’s an important one: get screened for the hepatitis C virus (HCV). More than 3 million Americans are infected with HCV, but the vast majority of them don’t know it. In my blog last May, Call for Wider Hepatitis Screenings, I first … Continue reading »

Research

Serum Vitamin D Levels Are Not Predictive of the Progression of Chronic Liver Disease in Hepatitis C Patients with Advanced Fibrosis

Emerging data suggest that vitamin D is an important modulator of both the inflammatory response and wound healing. [2], [3] Vitamin D may modulate the inflammatory response and subsequent fibrosis via inhibition of TNF-α, a cytokine that plays a central role in the regulation of the immune response [4], [5] and by inhibiting the development of fibrosis directly through suppression of TGF-β, a multifunctional cytokine that may influence fibrosis progression [6].[7].[8].

The importance of vitamin D in immune modulation and deposition of fibrosis may extend to the liver, which plays an important role in vitamin D homeostasis. The liver is the site of the conversion of vitamin D3 to 25-hydroxy-vitamin D (25-OH-vitamin D) and may be a site of vitamin D storage. [9] In addition, vitamin D receptors exist on hepatocytes and other hepatic parenchymal cells, including hepatic stellate cells. As in the kidney, vitamin D is postulated to play an antiinflammatory and antifibrotic role in the liver via binding to promoters of target genes, leading to down-regulation of TNF-α and TGF-β production.

Cross-sectional population data suggest that vitamin D deficiency is common in persons with advanced liver disease. [10], [11] For example, Fisher et al. [12] evaluated vitamin D levels in 100 patients with liver disease, 51 with cirrhosis and 49 without cirrhosis, including 38 patients with chronic hepatitis C. The prevalence of vitamin D deficiency was significantly higher in cirrhotic than noncirrhotic subjects (86.3% versus 49.0%, p = 0.0001). Moreover, vitamin D levels decreased with advancing Child class; vitamin D levels were significantly lower in subjects with Child class C (22.7 nmol/L) than in those with Child class A (45.8 nmol/L, p<0.001). Such studies, however, are limited by their cross-sectional nature. Thus, while an association between vitamin D deficiency and advancing liver disease has been noted, the potential that vitamin D deficiency could be a predictor for progressive liver disease has not been explored.

Recently, vitamin D has been evaluated as a potential immunomodulator of hepatitis C virus (HCV), and preliminary data suggest that the addition of vitamin D to standard antiviral therapy may improve treatment response rates. [13] This observation lends further weight to the potential immunomodulatory role of vitamin D in liver disease.

The progression of hepatic fibrosis occurs over years, hampering the study of processes that affect fibrosis. On the other hand, the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial provided a unique opportunity to study fibrosis longitudinally over several years. [14] The HALT-C Trial was a 10-clinical center randomized, controlled trial to evaluate the benefit of long-term (3.5-years) peginterferon therapy in patients with histologically advanced (Ishak fibrosis stage ≥3) but clinically compensated chronic hepatitis C who had failed to respond previously to antiviral therapy. While the HALT-C Trial was a negative study, showing that such maintenance antiviral therapy was ineffective, the trial's study design, including sequential liver biopsies spanning 4 years rendered the trial population ideally suited for the study factors that might influence fibrosis progression. Therefore, we conducted a nested case-control study of vitamin D levels in subjects with and without liver histologic progression or clinical decompensation over the course of the HALT-C Trial.

Genetic polymorphisms near IL28B are associated with spontaneous and treatment-induced clearance of hepatitis C virus (HCV), 2 processes that require the appropriate activation of the host immune responses.

Intrahepatic inflammation is believed to mirror such activation, but its relationship with IL28B polymorphisms has yet to be fully appreciated.

Dr Francesco Negro and colleagues from Switzerland analyzed the association of IL28B polymorphisms with histological, and follow-up features in 2335 chronically HCV-infected Caucasian patients.

The G allele at IL28B marker rs8099917 was associated with lower fibrosis

The team evaluated associations of alleles with the phenotypes by univariate analysis and multivariate logistic regression, accounting for all relevant covariates.

The researchers found that the rare G allele at IL28B marker rs8099917 was associated with lower activity, lower fibrosis with a trend toward lower fibrosis progression rate.

When stratified according to HCV genotype, most significant associations were observed in patients infected with non-1 genotypes, where the odds ratio of having necroinflammation or rapid fibrosis progression for patients with IL28B genotypes TG or GG versus TT were 0.48, and 0.56, respectively.

The research team noted that IL28B polymorphisms were not predictive of the development of hepatocellular carcinoma.

LONDON (Dow Jones)--Hepatitis C, a harrowing infection that leads to the inflammation of the liver, is a virus of pandemic size that has attracted the attention of some of the world's biggest drug makers.

But Sweden's small biotech Medivir AB (MVIR-B.SK) says it intends to be a major player in treating the disease, and predicts the market will ultimately have room for just four or five products.

"It is simply a question of which drug will have the biggest share of the market", Medivir's executive vice-president of corporate affairs Rein Piir told Dow Jones Newswires in an interview.

And in protease inhibitor TMC435, Piir believes Medivir has found its winner.

Piir says there is nothing in development that's better than TMC435, which is currently in global Phase III trials and which Medivir expects to launch by the end of next year.

Danske Banke analyst Hans Jeppsson agrees.

Jeppsson regards TMC435 as being the best-in-class protease inhibitor, which prevents viral replication by inhibiting the activity of protease enzymes. Final judgment will need to await results from two combination trials the drug is currently undergoing, he adds.

Around 170 million people are infected worldwide with Hepatitis C, a disease that can be transmitted sexually, through shared needles or through infected blood transfusions.

Thousands of people in Japan were infected with Hepatitis C between the 1970s and 1990s due to tainted blood clotting agents and the country remains one of the most hepatitis C-dense in the world. Due to the high numbers of hepatitis C sufferers in Japan, the country is "as important commercially" to Medivir as Europe, Piir says.

Other countries with a high prevalence of Hepatitis C include Egypt, where around 20% of blood donors are anti-HCV positive, and areas of Italy.

Medivir's Piir believes that the future treatment of Hepatitis C will involve a combination of protease inhibitors; inhibitors of nucleotides, which are molecules that, when joined together, make up the structural units of RNA and DNA; and inhibitors of NS5A, a non structural viral protein found in Hepatitis C.

NS5A inhibitors currently in development include Bristol-Myers Squibb's (BMY) BMS790052, and Gilead Sciences Inc's (GILD) GS-7977. However, Gilead recently reported that a majority of patients in a clinical trial of GS-7977 had experienced a relapse in their disease after being treated with the product, raising questions about the market potential of the drug and the wider class of NS5A inhibitors.

A protease inhibitor currently used to treat HCV genotype 1 infection, the most common and hardest-to-treat type of Hepatitis C is Vertex Pharmaceuticals' (VRTX) and Johnson & Johnson's (JNJ) telaprevir, though, unlike TMC435, it must be administered in combination with pegylated interferon alpha and the antiviral drug ribavirin. Its safety profile has also been criticized, whereas TMC435 has to-date been generally safe and well tolerated, according to Medivir.

The Swedish biotech floated on the Nasdaq OMX Stockholm index in 1996 and currently has a market capitalization of around SEK2.1 billion ($320.2 million).

“We believe EDP-239 has great potential as a potent ingredient in combination drug therapy, and our preclinical studies have demonstrated high potency against multiple genotypes of the virus, excellent safety profile, and a preclinical pharmacokinetic profile amenable to once-a-day dosing in humans,” said Jay Luly, president and CEO of Enanta Pharmaceuticals.

TAK-875, a new treatment for type 2 diabetes, improves blood sugar control and is equally effective as glimepiride, but has a significantly lower risk of creating a dangerous drop in blood sugar, called hypoglycemia, according to a new study.

The results of the phase 2 randomized trial were published Online First Sunday in The Lancet.Type 2 diabetes is the most common form of diabetes accounting for 90 percent of the 150 million people in the United States currently living with the disease. It is primarily caused by a lack of response to insulin which leads to high blood sugar and a variety of chronic conditions.
Free fatty acid receptor 1, also known as G protein-coupled receptor 40, or GPR40, plays a vital role in stimulating and regulating the production of insulin.

It works by boosting the release of insulin from pancreatic β-cells when glucose and fatty acids rise in the blood, such as after a meal, which results in a fall in blood glucose levels. Drugs that activate the FFAR1 receptor have the potential to help diabetics release more insulin and improve control of blood glucose levels.

TAK-875 is a novel oral medication designed to enhance insulin secretion in a glucose-dependant manner, which means that it has no effect on insulin secretion when glucose levels are normal, and as such has the potential to improve the control of blood sugar levels without the risk of hypoglycemia.
In the study, Charles Burant, M.D., Ph.D., professor of internal medicine at the University of Michigan Health System, and colleagues randomly assigned 426 patients with type 2 diabetes who were not achieving adequate glucose control through diet, exercise or metformin treatment to one of five doses of TAK-875, a placebo, or glimepiride, a conventional diabetes treatment. The primary outcome was change in hemogloblin A1c from the start of the study.

At 12 weeks, all doses of TAK-875 resulted in significant drops in HbA1c compared with placebo. A similar reduction occurred in patients given glimepiride.

At a TAK-875 dose of 25 mg or higher, about twice as many patients (33 to 48 percent) reached the American Diabetics Association target of HbA1c less than 7 percent within 12 weeks, compared with placebo (19 percent) and was similar to glimepiride (40 percent).
TAK-875 was generally well-tolerated. The incidence of hypoglycaemia was significantly lower for all doses of TAK-875 compared with glimepiride (2 percent compared to 19 percent), and was similar to placebo which was 2 percent.

The overall incidence of treatment-related side effects was similar for the TAK-875 groups and placebo groups (49 percent; all TAK-875 groups vs 48 percent), but higher in the glimepiride group (61 percent) because of the increased risk of hypoglycaemia.

The authors say: “In view of the frequent hypoglycemia after treatment with sulfonylureas,the low-risk of hypoglycaemia after treatment with TAK-875 suggests that there may be therapeutic advantage of targeting FFAR1 in treating people with type 2 diabetes.”
They conclude:“We are truly excited about the potential of TAK-875 and are eager to conduct larger trials to find out how well this drug works, how safe it is and what its place is in the treatment of diabetes.

“TAK-875 significantly improved glycemic control in patients with type 2 diabetes with minimum risk of hypoglycemia. The results show that activation of FFAR1 is a viable therapeutic target for treatment of type 2 diabetes,” authors say.

Disclosure: Burant is an unpaid consultant and advisor to Takeda Global Research and Development which discovered TAK-875.

SummaryBackground
The nonstructural 3 serine protease inhibitors (PIs), boceprevir and telaprevir, represent the first in a new generation of directly acting antivirals against genotype 1 hepatitis C (HCV) infection. When used in combination with pegylated interferon and ribavirin, these drugs greatly improve sustained virological response rates in both treatment-naïve patients and patients who have had previous virological failure on treatment. However, the addition of these new agents will increase the complexity of therapeutic regimens, the rates of side-effects and costs.Aims
To review concisely the current evidence and to suggest current best practice, for the use of telaprevir and boceprevir in the management of chronic genotype 1 HCV infection.Methods
These guidelines for the use of boceprevir and telaprevir have been formulated following extensive review of the current literature, are based on the consensus opinion of a panel of national experts, and have been openly discussed and debated at a national meeting of HCV care providers.Results
We have made recommendations on a number of the key practical issues facing HCV care providers: (i) Which patients to treat?; (ii) Standards for the provision of care; (iii) Pre-treatment considerations; (iv) Which treatment regimens to use?; (v) Stopping rules; and (vi) Management of adverse effects. Finally, we have produced suggested algorithms for the assessment and treatment of these patients.Conclusions
These UK Consensus guidelines indicate the current best practice for the use of boceprevir and telaprevir in the management of genotype 1 chronic HCV infection.

Introduction

Chronic hepatitis C infection (HCV) affects around 200 million people worldwide.[1, 2] It is estimated that up to 30% of these patients will develop cirrhosis[3] and around 5% per year will develop decompensated liver disease or hepatocellular carcinoma.[4] Furthermore, chronic HCV infection remains one of the principal indications for liver transplantation, with an increasing incidence in the Western world.[5] Therefore, HCV infection already represents a major health burden, which is predicted to increase several fold in the next two decades.[6] Currently, there are six HCV genotypes recognised with several subtypes identified. Genotype 1 infection (subtypes 1a and 1b) represents the commonest cause of chronic infection in the world.[7]

The advent of dual therapy with pegylated interferon- (IFN-) and ribavirin resulted in a vast improvement in the treatment for chronic HCV infection. The current measure of successful therapy is to achieve a sustained virological response (SVR), defined as an undetectable serum HCV RNA level, 24 weeks after cessation of treatment. An SVR is typically associated with resolution of liver disease and improved quality of life in noncirrhotic patients, although cirrhotic patients may still be at risk of liver-related complications. The current standard of care (SoC) treatment for genotype 1 infected patients, with pegylated IFN- and ribavirin for 48 weeks, is associated with an SVR rate of between 40% and 50% in most clinical trials.[8, 9, 10] Although this is a significant advance over single-agent therapy, there remains a large number of patients who will not achieve an SVR. Furthermore, there have been very limited options for those patients who fail to clear the virus with initial dual therapy, retreatment with Peg IFN- and ribavirin, giving overall SVR rates of only between 10% and 20% in published studies.[11, 12, 13] Given the global scale of HCV infection, this remains a significant health problem, and novel therapies are required.

As the life cycle of the HCV virus has become known, novel therapeutic targets have been identified, enabling the development of directly acting anti-viral (DAA) drugs that are more specific than standard treatment regimes. The nonstructural 3 serine protease inhibitors (PIs), telaprevir (Incivo, Janssen-Cilag SpA, Borgo San Michele, Italy) and boceprevir (Victrelis, MSD, Hoddeston, UK), directly inhibit viral replication and may also restore the natural innate immune response of hepatocytes.[14] Large phase 3 trials of both these PIs in patients with chronic infection with genotype 1 HCV have shown highly significant increases in the proportion of patients who obtain an SVR. These drugs have been recognised as a major advance in the treatment of patients infected with genotype 1 hepatitis C virus, and therefore, have been approved for use by the FDA, EMA and Scottish Medicines Consortium (SMC).

These guidelines for the use of boceprevir and telaprevir have been formulated following extensive review of the current literature, are based on the consensus opinion of a panel of national experts, and have been openly discussed at a national meeting of HCV care providers. They aim to concisely summarise the current evidence and to suggest current best practice, for the use of telaprevir and boceprevir in the management of chronic genotype 1 HCV infection.

Efficacy of Protease Inhibitor-Based Therapy

A number of high quality clinical trials have now been published, examining the efficacy of the addition of PIs to SoC treatment for both treatment-naïve patients and patients who have had previous virological failure. Evidence only currently exists for the use of these drugs in Genotype 1 infected patients. Furthermore, all the trial data quoted is on an intention to treat basis, including patients who received at least one dose of any study drug.

Treatment-naïve patients

The efficacy of boceprevir in treatment-naïve genotype 1 infected patients has been demonstrated in phase 2 (SPRINT-1)[15] and phase 3 (SPRINT-2)[16] clinical trials. SPRINT-1 included 520 patients who were randomly assigned to one of five groups: PR48 (SoC receiving Peg IFN-2b 1.5 μg/kg and ribavirin 800–1400 mg daily for 48 weeks); PRB28 or PRB48 (SoC peginterferon-ribavirin and boceprevir 800 mg three times per day for 28 or 48 weeks respectively); PR4/PRB24 or PR4/PRB44 (SoC peginterferon-ribavirin lead-in for 4 weeks followed by triple therapy for 24 or 44 weeks respectively). SVR rates were as follows: PR48 Control = 38%; PRB28 = 54%; PRB48 = 67%; and PR4/PRB24 = 56%; PR4/PRB44 = 75%, indicative of significantly enhanced SVR with the addition of boceprevir (Table 1).

Click Table To Enlarge

In the phase 3 study, SPRINT-2, all 1097 patients received 4 weeks of lead-in treatment (SoC Peg IFN-α2b 1.5 μg/kg and ribavirin 600–1400 mg daily) followed by randomisation to three groups: Group 1 (control receiving 44 weeks SoC peginterferon-ribavirin and placebo), Group 2 (response-guided therapy with SoC peginterferon-ribavirin and boceprevir 800 mg t.d.s for 24 weeks with those having detectable HCV RNA at any visit between 8 and 24 weeks continuing on SoC peginterferon-ribavirin for an additional 20 weeks) and Group 3 (SoC peginterferon-ribavirin and boceprevir for 44 weeks). SVR rates were as follows: Group 1 = 38%; Group 2 = 63%; and Group 3 = 66% (Table 1). Thus, in both phase 2 and phase 3 studies, the addition of boceprevir to standard dual therapy in treatment-naïve patients results in increase SVR rates by a minimum of 25%. Furthermore, the use of response-guided treatment (RGT) with boceprevir is associated with an improved SVR (compared with dual therapy) despite a shorter duration of treatment.

Similar studies have been carried out for telaprevir in patients with genotype 1 chronic HCV infection. In the PROVE1 study,[17] 233 patients received one of the following three treatments: PR48 (SoC Peg IFN-α2a 180 μg/week and ribavirin 1000–1200 mg daily for 48 weeks), T12PR24 and T12PR48 (Telaprevir for 12 weeks with SoC peginterferon-ribavirin followed by SoC peginterferon-ribavirin alone for 12 and 36 additional weeks respectively). SVR rates were as follows: PR48 = 41%, T12PR24 = 61% and T12PR48 = 67% (Table 1). Similar findings were seen in PROVE2,[18] where SVR rates for PR48 (control) and T12PR24 groups were 46% and 69% respectively (Table 1). Importantly, both PROVE1 and PROVE2 studies demonstrated that shortening the duration of peginterferon-ribavirin to 12 weeks to match duration of telaprevir therapy reduced SVR to that of standard dual therapy.[17, 18] Furthermore, in a separate treatment arm, PROVE2 showed that ribavirin was essential to reduce the risk of relapse and viral breakthrough with telaprevir treatment.[18]

In the phase 3 ADVANCE study,[19] a total of 1088 patients were randomised to three treatment groups: PR group (SoC Peg IFN-α2a 180 μg/week and ribavirin 1000–1200 mg daily for 48 weeks), T8PR and T12PR groups (SoC peginterferon-ribavirin and telaprevir for 8 or 12 weeks, respectively, followed by SoC peginterferon-ribavirin alone in a response-guided manner, with patients who had an eRVR (negative HCV RNA at 4 and 12 weeks) continuing treatment up to week 24, whereas those who had positive HCV RNA at either 4 or 12 weeks continuing SoC peginterferon-ribavirin treatment up to week 48. The SVR rates were as follows: PR group = 44%, T8PR = 69% and T12PR = 75% (Table 1). Thus, overall, addition of telaprevir to standard dual therapy regimens in treatment-naïve patients results in improved SVR rates by at least 20–25%, a similar efficacy to boceprevir-based regimens.

In conclusion, phase 2 and 3 studies using boceprevir and telaprevir in treatment-naïve patients in addition to peginterferon-ribavirin, shows a robust increase in overall SVR rates of at least 20–25%. Whilst the regimens used differ between studies, the efficacy of boceprevir and telaprevir is largely similar. Furthermore, in the larger phase 3 studies (SPRINT-2 and ADVANCE), response-guided therapy seems equally effective and may enable shortened treatment durations in specific groups of patients. In addition, the SVR rates have been improved in the phase 3 compared with phase 2 studies, indicative of better management of adverse effects and higher concordance rates as a result of improved physician experience and education.

Patients who have had virological failure with previous treatment

As discussed above, a significant proportion of patients will not achieve an SVR with current SoC treatment due to virological failure. These patients can broadly be divided into three groups:

Virological relapse: Patients who have undetectable HCV RNA at the end of treatment, but do not achieve an SVR (i.e. detectable HCV RNA during follow-up period).

Virological partial response: Patients who have a ≥2 log10 IU/mL drop in HCV RNA by 12 weeks of treatment, but never achieve undetectable HCV RNA

Virological null response: Patients who have a <2 log10 IU/mL drop in HCV RNA by 12 weeks of treatment

Phase 2 and 3 studies have now been conducted using boceprevir and telaprevir in these patients who have not achieved an SVR despite prior treatment with combination antiviral therapy. In the RESPOND-2 study using boceprevir,[20] a total of 403 patients with previous relapse and partial response were recruited. Patients with previous null response were not included in this study. All patients received a lead-in treatment for 4 weeks with SoC Peg IFN-2b 1.5 μg/kg weekly and ribavirin 600–1400 mg daily. Patients were then randomised to three groups: Group 1 [control received SoC peginterferon-ribavirin for 44 additional weeks (total 48 weeks)] and Group 2 [response-guided therapy with all patients receiving SoC peginterferon-ribavirin and boceprevir for 32 additional weeks (up to week 36); those patients with undetectable HCV RNA at week 8 and 12 completed therapy at week 36, whereas those patients who had detectable HCV RNA at week 8 (but not at week 12) continued on SoC peginterferon-ribavirin until week 48]; Group 3 (SoC peginterferon-ribavirin and boceprevir for an additional 44 weeks). Overall SVR rates were Group 1 (control) = 21%, Group 2 (response-guided therapy) = 59% and Group 3 = 66%. Subgroup analysis indicated SVR rates (group 1 vs. 2 vs. 3) among patients with previous relapse of 29% vs. 69% vs. 75% and among patients with previous partial response of 7% vs. 40% vs. 52% (Table 2).

In summary, there is a significant benefit to retreating patients who have previously had virological failure with peginterferon-ribavirin therapy, using triple therapy with a protease inhibitor. Overall, this can improve SVR rates in these patients by over 40%. The benefits of protease inhibitor regimens over SoC treatment seem to hold for patients with prior relapse, partial response and null response, although the SVR rate is lower in prior partial responders and null responders. The regimens used for boceprevir and telaprevir differed between the studies, but showed similar SVR rates. Of note, boceprevir has not been used in patients with a prior null response.

Patients with nongenotype 1 HCV infection

Currently, there are very limited data for the use of DAAs in patients with nongenotype 1 HCV infection. Only a small proof of concept study has suggested some efficacy of telaprevir in Genotype 2 HCV infection, albeit fewer than 20 patients received the PI.[22] Therefore, currently neither boceprevir nor telaprevir should be used in patients with nongenotype 1 HCV infection.[23] Such patients may benefit from the ongoing development of the next generation of DAAs.

Cost-Effectiveness of PI Treatment

Clearly, the addition of PI treatment to the current SoC treatment of pegylated intereferon and ribavirin represents a major step forward in the treatment of genotype 1 chronic HCV infection. Viral eradication at any stage of liver disease, both cirrhotic and noncirrhotic, prevents disease progression and improves survival and quality of life whilst reducing the healthcare costs associated with the management of complications. However, PIs remain costly, boceprevir costing £2800 per month and telaprevir costing £7466 per month of treatment.1 Thus, a full treatment course of telaprevir (12 weeks fixed-duration) will cost £22 398, whereas a full treatment course of boceprevir will range from to £16 800 to £30 800 depending on the regimen used for a particular patient.

Full cost-effectiveness analyses are starting to emerge. The addition of boceprevir in treatment-naïve patients in SPRINT-2 regimens yielded an incremental cost-effectiveness ratio (ICER) of $24 017 for RGT treatment and $39 733 for fixed-duration treatment compared with SoC.[24] In treatment-experienced patients, managed according to RESPOND-2 regimens, the addition of boceprevir yielded an ICER of $27 900 for RGT and $33 395 for fixed-duration therapy when compared with peginterferon and ribavirin alone.[25] Similar data has been shown in an independent analysis by the Scottish Medicines Consortium (http://www.scottishmedicines.org.uk), where the ICERs of boceprevir in treatment-naïve patients were £18 225 (F0–F3 hepatic fibrosis) and £20 808 (F4 cirrhosis), whereas in treatment-experienced patients, ICERs were £15 668 (F0–F3 hepatic fibrosis) and £1683 (F4 Cirrhosis). Thus, from these initial analyses, boceprevir treatment seems to be cost-effective at current thresholds, in particular, for cirrhotic treatment-experienced patients and the use of RGT in either treatment-naïve patients or patients with previous virological failure. Given the similar efficacy and overall costs, these data are likely to be replicated with telaprevir. Interestingly, in a separate study, a cost-effectiveness analysis of the addition of telaprevir to peginterferon-ribavirin in genotype 1 infected patients with IL-28B CC genotype (high chance of cure with SoC regimes) demonstrated a lack of cost-effectiveness for the use of telaprevir in this group.[26] Thus, it is likely that in subgroups of patients who have a high chance of achieving an SVR with SoC therapy alone, the addition of a PI will not prove to be cost-effective at current thresholds.

Mathematical modelling has demonstrated that by increasing the cure rate to 80% and by treating 50% of HCV-infected patients, there will be a significant reduction of 34% in deaths due to liver disease.[6] Achieving such figures will have a massive impact on the disease burden in forthcoming years. Whilst, by addition of a PI, SVR rates can approach this 80% in certain groups, the number of patients being treated must continue to increase to make a meaningful impact at a population level.

Factors Predictive of Response to Treatment

Prior to deciding on appropriate treatment regimens, it is possible to predict those patients who are highly likely to respond to therapy (good response group) and those who are less likely to respond (poor response group). This will enable a more tailored approach to therapy. In HCV genotype 1 patients, 67–75% can now be cured, 38–46% can be cured with SoC alone, an additional 23–31% with the use of a PI, whereas 25% will still have treatment failure. If we had predictors that accurately identified these groups, therapy could, potentially, be made more cost-effective, and some patients would be spared unnecessary side-effects. Perfect predictors do not exist currently. However, it is possible to identify a subset of patients who have very high SVR rates with SoC alone, in whom the addition of a PI may have little additional benefit. These patients can be predicted on the basis of combinations of baseline clinical, viral and genetic characteristics.[27, 28, 29, 30] Alternatively, early viral response to peginterferon-ribavirin has high positive predictive value for cure and applies to a larger proportion of patients.[31, 32] However, the appropriate duration of therapy for such patients is still debated: a reduced duration of 24 weeks has been suggested from retrospective cohorts to show SVRs ranging from 80% to >90%,[33] whereas the trials of triple therapy have prospectively demonstrated SVRs of >90% with 6 months therapy.

Additionally, a number of characteristics associated with a poor SVR rate have been reported in the recent phase 3 PI studies (see Table 3). These are largely in keeping with previous data generated from SoC studies.[7, 27] Furthermore, recent subgroup analysis has identified a reduction in HCV RNA levels of <1 log10 after 4 weeks of lead-in peginterferon-ribavirin as a significant predictor of a reduced SVR rate, even with triple therapy.[16, 34] This is particularly low in patients with coexistent cirrhosis.

Summary of factors that have been shown to be associated with a poor response to protease inhibitor-based triple therapy. Factors that have a dominant effect have been classified as major factors. HCV, hepatitis C infection; SVR, sustained virological response.

Thus, by considering a number of baseline factors and monitoring the early viral response to peginterferon-ribavirin, it is possible to identify patients in the good response group who would gain little benefit from the addition of a PI, and those in the poor response group who may still have a low chance of cure even with the use of a PI and might be better served to await treatment with the next generation of DAAs.

Viral Resistance

The existing evidence from the use of DAAs in the treatment of HIV and hepatitis B infection indicates that viral resistance is a major concern. HCV is clearly a different virus, with numerous naturally occurring variants present at any one time as a result of the high replication rate. These variants can confer resistance to DAAs by altering the drug binding site.[35] The administration of DAAs may then lead to the resistant mutant becoming the dominant viral strain, causing virological failure of treatment. Furthermore, these viral strains may subsequently develop additional resistance mutations that may render a class of DAAs redundant, potentially compromising future therapeutic options and the chance of cure. The impact of resistance in HCV to PIs is yet to be delineated.

From the studies to date, it seems that peginterferon and ribavirin administration is critical to preventing HCV resistance to PIs. In early phase 1 studies, monotherapy with either boceprevir[36] or telaprevir[37, 38] was associated with the emergence of viral resistance mutations, which were diminished when the PI was combined with peginterferon. Furthermore, in the SPRINT-2 study, patients who were less responsive to the lead-in peginterferon-ribavirin phase (<1 log10 decline in HCV RNA by week 4) showed significantly higher levels of virological failure and resistance mutations.[16] In addition, in the PROVE2 study, patients who had treatment with peginterferon and telaprevir without ribavirin showed lower SVR rates, with increased resistant mutations.[18] These data indicate that currently, PIs should only be used in combination with peginterferon and ribavirin to maximise SVR rates and minimise the development of resistance mutations.

Resistance mutations are also more likely to develop with ongoing exposure to PIs when treatment is futile. Thus, all of the studies to date enforce strict stopping rules, based on inadequate virological responses, when PI treatment should be discontinued to prevent ongoing exposure to the drugs when the chance of cure is very low. These rules vary between treatment regimens, but should be robustly adhered to in clinical practice.

The long-term consequences of these resistance mutations remain uncertain. It does seem that the HCV resistant variants decline with time off therapy, and become undetectable in the majority of cases during long-term follow-up.[39, 40] However, it is not clear if further administration of PIs to these patients might lead to rapid re-emergence of the resistant HCV or how they might respond to newer DAAs.

Thus, in the new era of PI therapy for chronic genotype 1 HCV infection, it is important to be aware of the potential for viral resistance, as this might adversely affect patient outcome now and in the future. This can be minimised by strict adherence to therapeutic regimens and stopping rules.

Adverse Effects

Whilst the appropriate use of PIs with peginterferon-ribavirin provides significant increases in cure rates of genotype 1 chronic HCV infection, there is also an increased rate of adverse effects with the use of triple therapy.

As indicated (Table 4), the principal side-effects associated with boceprevir treatment are dysgeusia (altered sense of taste), anaemia and neutropenia. The dysgeusia does not usually need any alteration in treatment. Dose reduction of boceprevir should not be used in the management of adverse effects, as suboptimal dose will promote the emergence of resistant species in failing regimens.

Click Table To Enlarge

With telaprevir treatment regimens, the adverse effect profile is slightly different from boceprevir (Table 5). Studies have shown an increase in skin rash (see below) and anorectal symptoms (discomfort and pruritus) with telaprevir treatment. The anorectal symptoms are usually tolerable for the duration of telaprevir treatment, and rarely (0.5%) led to discontinuation.

Click Table To Enlarge

Anaemia in PI treatment

Treatment with either PI is associated with an increased rate of anaemia compared with SoC. As shown (Table 4), there was a 20–26% increase in the rate of anaemia in boceprevir-treated patients compared with SoC. However, the rate of severe anaemia (Grade 3 or 4: Hb <8 g/dL) remained low with overall rates of 3–7% in boceprevir groups (compared to 1–2% in SoC) with only 2–3% of patients discontinuing treatment due to anaemia (compared with 0–2% in control arms).[16, 20] In boceprevir trials, erythropoietin use was actively encouraged with the provision of free drug to manage anaemia. Furthermore, dose reductions in ribavirin have not been shown to have an adverse effect on SVR rates.

In the telaprevir-treated patients, there was a 15–21% increase in the rate of anaemia compared with SoC (Table 5). The lower anaemia rate may in part reflect the shorter duration of triple therapy with telaprevir compared with boceprevir. Similar rates of severe anaemia (Grade 3 or 4) were seen compared with boceprevir treatment and only resulted in discontinuation of telaprevir in 2–4% of cases.[19, 21, 41] In the studies to date, the use of erythropoietin was not permitted in combination with telaprevir. Importantly, dose reduction of ribavirin is not associated with reduced SVR rates in combination with telaprevir.[42] Interestingly, the appearance of anaemia during treatment with SoC or triple therapy, with either PI, does not have a negative effect on SVR, but rather, has been shown to be positively associated with an increased chance of SVR.

Rash in PI treatment

One of the principal adverse events in telaprevir treatment is rash (Table 5). This leads to discontinuation of telaprevir in 5–7% of cases,[19, 21, 41] at which point the rash invariably resolves (although this may take several weeks). The rash is predominantly eczematous and pruritic. Fifty percent of patients developing rash do so within the first 4 weeks of treatment, although it can occur at any time. Rashes have been divided into:

Mild localised.

Moderate

Severe affecting >50% surface area or mucous membranes or with systemic symptoms

In the treatment strategies discussed, particularly when using response-guided therapy (RGT) and assessing stopping rules, a critical requirement for determining ongoing management is undetectable HCV RNA. In the clinical trials, highly sensitive PCR assays were used, with a lower limit of detection of 9.3–15 IU/mL,[15, 16, 17, 19, 20, 21] which are not always widely available in clinical practice. The use of less sensitive assays with PI treatment may lead to errant classification of HCV RNA as undetectable, which may inappropriately reduce treatment duration or lead to ongoing exposure to PIs when treatment is futile, increasing the risk of resistance mutations. Unsurprisingly, such misclassification would have an adverse effect on SVR rates.[43]

Furthermore, in clinical practice, there is often a delay from the time of sampling to receiving the HCV RNA quantification. When using these RNA titres as treatment decision points, this can cause a delay in initiating changes to therapy, which again may lead to unnecessary exposure to PIs, and hence a higher risk of viral resistance and increased cost. Therefore, rapid turnaround in laboratory assays is required.

Consensus Statements

Which patients to treat?

Due to the improvements in cure rates and potential for shortened therapy, protease inhibitor-based regimens should be considered for all genotype 1 chronic HCV-infected patients. This is applicable for treatment-naïve patients and patients who have had virological failure following prior exposure to SoC therapy

Where resources determine that there may be a delay in initiation of treatment, priority for PI treatment should be based on clinical need. Specific consideration should be given to patients likely to develop complications in the next 5 years or who have other pressing need for early therapy (e.g. concerns regarding fertility or disabling nonhepatic consequences of infection). Conversely, certain patients with a good liver prognosis may, following discussion, elect to wait for novel therapies.

Nongenotype 1 chronic HCV-infected patients should be treated without a PI, according to SoC regimens.

To prevent the predicted increase in deaths from liver failure and hepatocellular carcinoma due to chronic HCV infection, epidemiology and disease modelling indicates that we need to continue to increase the number of patients treated and cured.[44]

The adoption of PI-based regimens should not reduce the total number of HCV-infected patients being treated and cured.

The provision of care

Due to the importance of RGT and stopping rules in PI-based regimens and the increased risk of adverse effects, the use of PI treatment should be limited to centres providing the following standards of care:

Adherence to national standards for HCV.

Continuous audit of SVR rates to therapy.

Continuous audit of treatment discontinuation rates.

A high level of expertise in the use of anti-viral drugs.

Access to viral load estimation results within five working days of sampling.

Access to HCV PCR with a lower limit of detection of at most 15 IU/mL.[43]

Sufficient specialised medical and nursing staff to provide year round support to patients on therapy.

A series of protocols to minimise the risk of developing and to manage adverse reactions to therapy.

A comprehensive and skilled consultation service for patients emphasising the risks and benefits of therapy along with the requirement for adherence.

Where possible, all patients should be invited to participate in ongoing research initiatives (e.g. enrolment to the HCV research UK3 database).

Ongoing recruitment to clinical trials should continue where feasible.

Pre-treatment considerations

Assessment of likelihood of response.

All patients should have an assessment including baseline viral titres, an assessment of disease stage/cirrhosis (using non-invasive means or biopsy) and other demographic factors (see Table 3).

IL-28B genotyping and subtyping of HCV virus (1a or 1b) have some predictive value for treatment response, and may be used with other data to assist management discussions with patients about therapy, but are not required for treatment decisions.

In previously treated patients, if the data are available to determine the degree of prior response, this should be used to aid decision on treatment duration.

Co-morbid conditions.

HIV co-infected patients are at risk of rapid liver disease progression. Although no large scale clinical trial data currently exists, relevant drug interactions have been studied and treatment with PIs may be considered by expert physicians on a case-by-case basis, with active recruitment to ongoing clinical trials where available or audit of outcomes.

Protease inhibitor-based triple therapy can not currently be recommended in patients with decompensated liver disease, hepatitis B co-infection, active cancer or post-transplant due to limited data. The use of protease inhibitor triple therapy regimens in these groups should be the subject of new clinical trials.

Caution should be exercised in using PI treatment in patients with significant baseline neutropenia (<1200/mm3), thrombocytopenia (<90 000/mm3) or anaemia (Hb <12 g/dL for females or Hb <13 g/dL for males).

Due to potentially dangerous drug–drug interactions, dual peginterferon and ribavirin therapy might be considered more appropriate for some patients where there are serious concerns regarding these interactions with prescribed or illicit medication.

Dual therapy should be considered in conditions that impair adherence to therapy and thus reduce the effectiveness of triple therapy and increase the risk of development of resistance mutations.

Depression does not appear to be increased with PI treatment, but should be considered and monitored as per SoC treatment regimes.

Drug interactions.

Both boceprevir and telaprevir are metabolised by the CYP450 system, and are therefore prone to a number of drug–drug interactions. Evidence in this area is rapidly accumulating from ongoing studies.

Prior to prescribing a PI, a careful drug history (prescribed and nonprescribed) should be taken and relevant prescribing information and databases (e.g. www.hep-druginteractions.org) should be consulted for any potential drug–drug interactions. Primary Care providers need these issues specifically highlighted to avoid potentially ‘toxic’ interactions on therapy.

Which treatment regimens to use?Which peginterferon-ribavirin to use?
The treatment regimens used differ between the two PIs and the different trials. One critical difference between the studies is the use of different peginterferon-ribavirin preparations and doses. In general, in the boceprevir studies, pegylated IFN-2b (PegIntron; Merck, Whitehouse Station, NJ, USA) at a dose of 1.5 μg/kg once weekly and ribavirin (Rebetol; Merck) at weight-based dose of 600–1400 mg daily in two divided doses were used. In the telaprevir studies, pegylated IFN-2a (Pegasys; Roche, Welwyn Garden City, UK) at a dose of 180 μg/week and ribavirin (Copegus; Roche) at a weight dependent dose of 1000 mg (<75 kg) or 1200 mg (≥75 kg) per day were used. Direct comparison studies between Peg IFN-2a and Peg IFN-2b in SoC treatment have not shown any significant difference in overall response rates.[10] Furthermore, in small studies, telaprevir has been used with Peg IFN-2b[45] and boceprevir with IFN-2a[46] with no detrimental effect.

Peg IFN-2a or Peg IFN-2b can be used interchangeably with either telaprevir or boceprevir according to local preferences.
Ribavirin brands can be used interchangeably in treatment regimens.

Which protease inhibitor to use?
The documented evidence clearly shows a benefit for the use of either boceprevir or telaprevir as part of a triple therapy regimen in both treatment-naïve patients and patients with previous virological failure. Largely, the magnitude of beneficial effect is similar for either drug. No direct comparison studies between boceprevir and telaprevir have been conducted, and thus, neither drug can be recommended over the other. However, specific characteristics of each drug may lead to their use in certain circumstances. Boceprevir-based regimens use a 4-week lead-in with peginterferon-ribavirin, which may offer extra information on treatment tolerability and the likelihood of achieving an SVR. In addition, differences in side-effect profiles and the duration of treatment may lead to the choice of either PI for specific patients. Furthermore, the pill burden for patients differs, with boceprevir currently four tablets t.d.s., whereas telaprevir is two tablets t.d.s. It is therefore important that both drugs are available to treating units to enable selection of the most appropriate regimen for individual patients.

Both boceprevir and telaprevir are effective and should be available for use by treating units.
Which regimens to use?
As discussed above, triple therapy regimens with either boceprevir or telaprevir for genotype 1 chronic HCV-infected patients significantly improve SVR rates in both treatment-naïve and experienced patients. Some treatment-naïve patients achieve high SVR rates with SoC treatment alone. Specifically, noncirrhotic genotype 1 patients who have a low baseline viral load (<400 000–800 000 IU/mL) and achieve an RVR (HCV RNA undetectable (≤50 IU/mL) at 4 weeks of treatment) with peginterferon-ribavirin are highly likely (80–90%) to achieve an SVR. Indeed, the achievement of an RVR and low basal viral loads are the most significant predictors of achieving an SVR with SoC treatment,[47] and recent guidelines would suggest that treatment duration with peginterferon-ribavirin in these patients could be shortened to 24 weeks.[7] Thus, such good response group patients may not gain much additional benefit in SVR rates from the addition of a PI, but will be exposed to the increased side-effects and risks of resistance. Furthermore, the use of PIs in this group of patients is unlikely to be cost-effective (see above).

As discussed, some of the protease inhibitor clinical trial arms compared response-guided therapy (RGT) with fixed-duration therapy. In treatment-naïve patients, both the SPRINT-2 and ADVANCE studies showed that response-guided therapy had no detrimental effect on overall SVR rate. Furthermore, using RGT in the ADVANCE study enabled reduced treatment duration to 24 weeks in 58% of patients. In addition, the ILLUMINATE study demonstrated that in patients who achieve an eRVR (undetectable HCV RNA at treatment weeks 4 and 12) on telaprevir-based triple therapy, overall treatment can be reduced to 24 weeks with no detrimental effect on SVR rate.[41] In treatment-experienced patients, in the RESPOND study, no statistically significant differences were seen with boceprevir between the RGT arm and the fixed-duration therapy of 48 weeks. However, nonsignificant trends were observed to better SVR rates in the 48 week treatment duration in both prior relapsers and partial responders. In the REALISE study, no RGT arm was included.

The presence of advanced hepatic fibrosis or cirrhosis is a major risk factor for treatment failure. In the PI studies comparing RGT with fixed-duration treatment, the number of patients with cirrhosis is generally small. Furthermore, in these patients, there are nonsignificant trends towards better SVR rates with fixed-duration therapy.[16, 20, 41] Therefore, there is currently insufficient evidence for the use of RGT in cirrhotic patients.

The most difficult to treat group of patients, cirrhotic prior null responders, were only specifically studied in the REALISE trial, with fairly modest numbers.[21] Whilst there was an improved outcome in these patients with telaprevir-based triple therapy compared with SoC, the SVR rate was still only 22–28%. Furthermore, relapse rates were high (25–27%) with even higher levels of virological failure (47–57%), predominantly due to the emergence of resistant variants. Detailed analysis of the lead-in peginterferon-ribavirin T12PR48 group demonstrated that in prior null responders, poor response to lead-in therapy (<1 log10 reduction in HCV RNA at week 4) was also predictive of a poor SVR rate of under 20%.[21] Similarly, in RESPOND-2, a poor response to lead-in peginterferon-ribavirin was associated with low SVR rates in prior partial responders.[20] Therefore, whilst improved over previous therapies, SVR rates are likely to remain low in cirrhotic prior null responders, particularly in the context of a poor response to lead-in peginterferon-ribavirin. Treating these patients with PIs is also likely to increase development of resistance mutants, potentially jeopardising the use of future DAAs. Therefore, careful consideration should be given to the best management option for this group.

Regimens in treatment-naïve patients (see Figure 1).
Either boceprevir or telaprevir can be used according to the relevant prescribing information.
In noncirrhotic treatment-naïve patients with low baseline viral loads (<800 000 IU/mL) and no additional risk factors for treatment failure, who are treated with regimens incorporating a 4 week lead-in with peginterferon-ribavirin and who achieve an RVR following lead-in, consideration can be given to continuing treatment with SoC therapy alone without addition of a PI. This decision should be made following a balanced discussion with the patient regarding the rates of SVR and the potential side-effects from the addition of a PI.
Response-guided therapy with either boceprevir or telaprevir can be used in noncirrhotic treatment-naïve patients, enabling reduced treatment duration in a proportion of patients with no adverse effects on SVR. This should be done according to the relevant prescribing information.
In cirrhotic treatment-naïve patients, a full 48 week course of treatment, incorporating 12 weeks of telaprevir or 44 weeks of boceprevir, should be instituted according to the relevant prescribing information

Figure 1. Proposed algorithm for the use of protease inhibitors in treatment-naïve HCV genotype 1 infected patients. Pre-treatment assessment should include careful consideration of lifestyle factors, co-morbid conditions, potential drug interactions (prescribed and nonprescribed) and assessment for the presence of cirrhosis (by non-invasive or invasive means). In noncirrhotic patients, the presence of factors predictive of a poor response to therapy should be evaluated (#IL-28B genotype; age; ethnic origin; BMI; Type 2 diabetes; HCV genotype 1a vs. 1b). *In noncirrhotic patients with no risk factors for a poor response to therapy, the decision to use a 4-week lead-in with peginterferon and ribavirin and to continue on SoC in those who achieve an RVR should only be taken following careful and balanced discussion with the patient.

Regimens in patients with previous virological failure (see Figure 2).
Either boceprevir or telaprevir can be used according to the relevant prescribing information.
Where no data are available on the degree of previous response, patients should be treated with a full treatment course as per prior null responders to maximise cure rates.
In patients with factors predicting poor treatment response, who also currently have a low risk of progressive liver disease, before therapy, a discussion should occur to consider watchful waiting as an alternative to PI treatment pending the development of new treatment options.

Figure 2. Proposed algorithm for the use of protease inhibitors in HCV genotype 1 infected patients who have had prior virological failure on treatment. Pre-treatment assessment should include careful consideration of lifestyle factors, co-morbid conditions, potential drug interactions (prescribed and nonprescribed), assessment for the presence of cirrhosis (by non-invasive or invasive means) and the presence of factors predictive of a poor response to therapy. Identification of the degree of previous response should be attempted. If this information is not available, patients should be considered as prior null responders to maximise cure rates. *In cirrhotic prior null responders, the decision to watch and wait for novel therapies or to use a 4-week lead-in with peginterferon and ribavirin to identify patients more likely to achieve an SVR should only be taken following careful and balanced discussion with the patient.

Stopping rules

Boceprevir-based regimens:

All treatment should be stopped if HCV RNA is >100 IU/mL at treatment week 12 (week 8 of boceprevir) or HCV RNA is detectable at treatment week 24 (week 20 of triple therapy).

If there is virological breakthrough4 or incomplete virological response and rebound,5 treatment with boceprevir should be stopped, but peginterferon-ribavirin may be continued up to 48 weeks at the discretion of the treatment team.

Telaprevir-based regimens:

All treatment should be discontinued in patients who have an HCV RNA level >1000 IU/mL after 4 weeks or 12 weeks of triple therapy.

All treatment should be discontinued if <2 log10 decline from baseline in HCV RNA levels after week 12 of triple therapy

All treatment should be discontinued if HCV RNA is detectable at any point between treatment week 24 and 44.

Telaprevir treatment should be stopped if there is virological breakthrough or incomplete virological response and rebound, but peginterferon-ribavirin may be continued at the discretion of the treatment team

In cirrhotic prior null responders treated with regimens incorporating 4 week lead-in peginterferon-ribavirin, who achieve an HCV RNA reduction of <1 log10 IU/mL following lead-in, consideration should be given to stopping treatment. This should be following a balanced discussion with the patient regarding the consequences of a delay in therapy, low SVR rates, high chance of resistance mutations and potential effects this might have on eligibility for next generation treatments (Figure 2).

Management of adverse effects

Common adverse effects such as dysgeusia (boceprevir) and anorectal symptoms (telaprevir) are usually tolerable, do not normally require any treatment and very rarely lead to discontinuation of therapy. The adverse effects requiring intervention are most commonly anaemia, neutropenia and rash.
Management of anaemia in PI treatment:

Anaemia (defined as Hb <10 g/dL) in the context of PI treatment should be managed using an escalating combination of:

Ribavirin dose reduction: it should be started at full treatment dose and dose reduction instituted for anaemia at decrements of 200 mg.

Reduction in dose of interferon, if bone marrow suppression is evident.

Erythropoietin administration may be considered and used until Hb > 12 g/dL.

Supportive treatment with blood transfusion should be considered in extreme circumstances.

The dose of protease inhibitor should not be reduced for managing anaemia. If required, due to the severity of anaemia, the PI should be stopped completely

Management of neutropenia.

Significant neutropenia (absolute neutrophil count <750/mm3) should be managed according to current practice for SoC treatment. Consideration should be given to dose reduction of Pegylated interferon.

The dose of protease inhibitor should not be reduced for managing neutropenia or bone marrow suppression. If required due to the severity of neutropenia, the PI should be stopped completely.

Moderate progressive: Stop telaprevir. Monitor for 7 days and consider stopping peginterferon-ribavirin if not improving.

Severe or SCARs: Stop all treatment. Urgent dermatology review.

Future Developments

Boceprevir and telaprevir, the first generation of DAAs for HCV to be widely used in clinical practice, represent major progress in management. These drugs are likely to be the first in a long line of DAAs, with newer PIs in addition to polymerase inhibitors, nucleoside analogues and NS5A inhibitors currently under development, with promising early results. Indeed, studies using interferon-free regimes with combinations of new DAAs in small numbers of patients have shown high rates of viral response, even in the difficult to treat groups such as prior null responders.[48, 49, 50] These exciting developments highlight the importance of judicious use of boceprevir and telaprevir, closely following the suggested regimens and stopping rules, so as not to negatively influence the possibility of treatment when the next generation of DAAs become available.

Conclusions
The advent of protease inhibitor-based triple therapy for chronic genotype 1 HCV infection heralds a new era of treatment for these patients. Cure rates are significantly enhanced, and there is now a viable therapeutic option for the large group of patients who previously failed SoC therapy. Clearly, the ongoing development of the second generation PIs and other directly acting antiviral drugs will yield further improvements in the future, but the judicious use of boceprevir and telaprevir in clinical practice will be invaluable for the management of chronic HCV infection in 2012.

Declaration of personal interests: A. A. has served as a clinical investigator, consultant and/or member of speakers’ bureau for companies Johnson and Johnson and MSD. K. A. has served as a clinical investigator, consultant and/or member of speakers’ bureau for companies, Janssen, MSD, Gilead, Abbott, Novartis, BMS, Praesido and Astellas, and has received research funding from Gilead, Roche, BMS and MSD. A. B. has served as a clinical investigator, consultant and/or member of speakers’ bureau for Roche, MSD, Gilead, BMS, Janssen and Novartis. J. F. D. has served as a clinical investigator, consultant and/or member of speakers’ bureau for companies Roche, MSD, Abbott, Janssen and Gilead, and has received research funding from Schering Plough, Roche, Abbott and MSD. G. R. F has served as a consultant and/or member of speakers’ bureau for Roche, Merck, Gilead, BMS, BI, Chugai and Novartis, and has received research funding from Roche and Chugai. A. F has served as a consultant and/or member of speakers’ bureau for companies Schering Plough, Janssen, MSD and Gilead. R. F. has served as a clinical investigator, consultant and/or member of speakers’ bureau for Janssen, MSD and Roche. P. C. H. has served as a clinical investigator, consultant and/or member of speakers’ bureau for Roche, MSD, Schering Plough, BMS, Gilead and Janssen. D. J. M. has served as a consultant to MSD and Janssen. S. D. R has served as a clinical investigator, consultant and/or member of speakers’ bureau for Roche, Merck and Janssen, and has received research funding from Roche. Declaration of funding interests: None.

HCV Education
Review learning activities, editorials, with new data about interferon-free regimens approved for HCV, as well as investigational drugs still in the pipeline. Links are provided to support, patient friendly information, clinical trials, peer-reviewed journals, videos, conferences with commentary, all updated on a continuous basis.

Users can search for a hepatitis C clinical trial by category (genotype), or learn how to evaluate a clinical trial and become familiar with commonly used terms. HCV Advocate offers an easy to navigate HCV Medications Blog as well, organized by HCV genotype

View each rebuttal and all ongoing media coverage. In June the HCV community was blindsided when an article with a somewhat "clickbait" headline was released by The Guardian. The Guardian reported on a systematic review published by the Cochrane Collaboration that suggested achieving SVR (cure) for patients using hepatitis C direct-acting antivirals (DAAs) doesn't correlate with any long term benefits.

The controversy over expensive new drugs for hepatitis C
Link to research and news articles addressing the high cost of hepatitis C drugs; insurance restrictions - private insurers/Medicaid - and availability of generic versions/India, Egypt and other lower-income countries or through online "buyers clubs"

Liver Cancer After Treatment For Hepatitis C
​Research demonstrates that while SVR markedly reduced liver-related complications and liver cancer, some long-term risk for liver cancer remained in those who were cured of Hepatitis C. But after direct-acting antiviral therapy does the risk of developing liver cancer increase?

Meeting Updates

April 19-23
The European Association for the Study of the Liver (EASL) International Liver Congress (ILC 2017)

Merck today announced its strategic decision to discontinue the development of the investigational combination regimens MK-3682B (grazoprevir/ruzasvir/ uprifosbuvir) and MK-3682C (ruzasvir/uprifosbuvir) for the treatment of chronic hepatitis C virus (HCV) infection. This decision was made based on a review of available Phase 2 efficacy data and in consideration of the evolving marketplace and the growing number of treatment options available for patients with chronic HCV infection

Two HCV Drugs to Be Discontinued
The Food and Drug Administration (FDA) announced that Rebetol(ribavirin; Merck) capsules and PegIntron (peginterferon alfa-2b; Merck) for Injection are being discontinued. The decision is business-related and not due to safety or efficacy issues with the drugs.

Rebetol is a nucleoside analogue indicated for chronic hepatitis C in combination with interferon alfa-2b (pegylated and nonpegylated), in patients ≥3 years of age with compensated liver disease. It is supplied as 200mg capsules in 56-, 70-, and 84-count bottles. The Rebetol discontinuation is effective February 1, 2016.
PegIntron is an antiviral indicated for treatment of chronic hepatitis C in patients with compensated liver disease. It is supplied as 50mcg/0.5mL, 80mcg/0.5mL, 120mcg/0.5mL, and 150mcg/0.5mL single-use vials and single-use pre-filled pens. No effective date is available for the PegIntron discontinuation.

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